Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging

Diagnostic errors in paediatric cardiac intensive care

AbstractIntroductionDiagnostic errors cause significant patient harm and increase costs. Data characterising such errors in the paediatric cardiac intensive care population are limited. We sought to understand the perceived frequency and types of diagnostic errors in the paediatric cardiac ICU.MethodsPaediatric cardiac ICU practitioners including attending and trainee physicians, nurse practitioners, physician assistants, and registered nurses at three North American tertiary cardiac centres were surveyed between October 2014 and January 2015.ResultsThe response rate was 46% (N=200). Most respondents (81%) perceived that diagnostic errors harm patients more than five times per year. More than half (65%) reported that errors permanently harm patients, and up to 18% perceived that diagnostic errors contributed to death or severe permanent harm more than five times per year. Medication side effects and psychiatric conditions were thought to be most commonly misdiagnosed. Physician groups also ranked pulmonary overcirculation and viral illness to be commonly misdiagnosed as bacterial illness. Inadequate care coordination, data assessment, and high clinician workload were cited as contributory factors. Delayed diagnostic studies and interventions related to the severity of the patient’s condition were thought to be the most commonly reported process breakdowns. All surveyed groups ranked improving teamwork and feedback pathways as strategies to explore for preventing future diagnostic errors.ConclusionsPaediatric cardiac intensive care practitioners perceive that diagnostic errors causing permanent harm are common and associated more with systematic and process breakdowns than with cognitive limitations.</jats:sec

Chronic Exercise Modifies Age-Related Telomere Dynamics in a Tissue-Specific Fashion

We evaluated the impact of long-term exercise on telomere dynamics in wild-derived short telomere mice (CAST/Ei) over 1 year. We observed significant telomere shortening in liver and cardiac tissues in sedentary 1-year-old mice compared with young (8 weeks) baseline mice that were attenuated in exercised 1-year-old animals. In contrast, skeletal muscle exhibited significant telomere shortening in exercise mice compared with sedentary and young mice. Telomerase enzyme activity was increased in skeletal muscle of exercise compared with sedentary animals but was similar in cardiac and liver tissues. We observed significant age-related decreases in expression of telomere-related genes that were attenuated by exercise in cardiac and skeletal muscle but not liver. Protein content of TRF1 was significantly increased in plantaris muscle with age. In summary, long-term exercise altered telomere dynamics, slowing age-related decreases in telomere length in cardiac and liver tissue but contributing to shortening in exercised skeletal muscle

Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells

AbstractDNA repair by nonhomologous end-joining (NHEJ) relies on the Ku70:Ku80 heterodimer in species ranging from yeast to man. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, Ku also controls telomere functions. Here, we show that Ku70, Ku80, and DNA-PKcs, with which Ku interacts, associate in vivo with telomeric DNA in several human cell types, and we show that these associations are not significantly affected by DNA-damaging agents. We also demonstrate that inactivation of Ku80 or Ku70 in the mouse yields telomeric shortening in various primary cell types at different developmental stages. By contrast, telomere length is not altered in cells impaired in XRCC4 or DNA ligase IV, two other NHEJ components. We also observe higher genomic instability in Ku-deficient cells than in XRCC4-null cells. This suggests that chromosomal instability of Ku-deficient cells results from a combination of compromised telomere stability and defective NHEJ

Mechanism of membrane fusion induced by vesicular stomatitis virus G protein

The glycoproteins (G proteins) of vesicular stomatitis virus (VSV) and related rhabdoviruses (e.g., rabies virus) mediate both cell attachment and membrane fusion. The reversibility of their fusogenic conformational transitions differentiates them from many other low-pH-induced viral fusion proteins. We report single-virion fusion experiments, using methods developed in previous publications to probe fusion of influenza and West Nile viruses. We show that a three-stage model fits VSV single-particle fusion kinetics: (i) reversible, pH-dependent, G-protein conformational change from the known prefusion conformation to an extended, monomeric intermediate; (ii) reversible trimerization and clustering of the G-protein fusion loops, leading to an extended intermediate that inserts the fusion loops into the target-cell membrane; and (iii) folding back of a cluster of extended trimers into their postfusion conformations, bringing together the viral and cellular membranes. From simulations of the kinetic data, we conclude that the critical number of G-protein trimers required to overcome membrane resistance is 3 to 5, within a contact zone between the virus and the target membrane of 30 to 50 trimers. This sequence of conformational events is similar to those shown to describe fusion by influenza virus hemagglutinin (a “class I” fusogen) and West Nile virus envelope protein (“class II”). Our study of VSV now extends this description to “class III” viral fusion proteins, showing that reversibility of the low-pH-induced transition and architectural differences in the fusion proteins themselves do not change the basic mechanism by which they catalyze membrane fusion

The Lyman alpha reference sample. VII. Spatially resolved Hα\alpha kinematics

We present integral field spectroscopic observations with the Potsdam Multi Aperture Spectrophotometer of all 14 galaxies in the $z\sim 0.1$ Lyman Alpha Reference Sample (LARS). We produce 2D line of sight velocity maps and velocity dispersion maps from the Balmer $\alpha$ (H$\alpha$) emission in our data cubes. These maps trace the spectral and spatial properties of the LARS galaxies' intrinsic Ly$\alpha$ radiation field. We show our kinematic maps spatially registered onto the Hubble Space Telescope H$\alpha$ and Lyman $\alpha$ (Ly$\alpha$) images. Only for individual galaxies a causal connection between spatially resolved H$\alpha$ kinematics and Ly$\alpha$ photometry can be conjectured. However, no general trend can be established for the whole sample. Furthermore, we compute non-parametric global kinematical statistics -- intrinsic velocity dispersion $\sigma_0$, shearing velocity $v_\mathrm{shear}$, and the $v_\mathrm{shear}/\sigma_0$ ratio -- from our kinematic maps. In general LARS galaxies are characterised by high intrinsic velocity dispersions (54\,km\,s$^{-1}$ median) and low shearing velocities (65\,km\,s$^{-1}$ median). $v_\mathrm{shear}/\sigma_0$ values range from 0.5 to 3.2 with an average of 1.5. Noteworthy, five galaxies of the sample are dispersion dominated systems with $v_\mathrm{shear}/\sigma_0 <1$ and are thus kinematically similar to turbulent star forming galaxies seen at high redshift. When linking our kinematical statistics to the global LARS Ly$\alpha$ properties, we find that dispersion dominated systems show higher Ly$\alpha$ equivalent widths and higher Ly$\alpha$ escape fractions than systems with $v_\mathrm{shear}/\sigma_0 > 1$. Our result indicates that turbulence in actively star-forming systems is causally connected to interstellar medium conditions that favour an escape of Ly$\alpha$ radiation.Comment: 26 pages, 15 figures, accepted for publication in A&

Interacting mindreaders

Could interacting mindreaders be in a position to know things which they would be unable to know if they were manifestly passive observers? This paper argues that they could. Mindreading is sometimes reciprocal: the mindreader's target reciprocates by taking the mindreader as a target for mindreading. The paper explains how such reciprocity can significantly narrow the range of possible interpretations of behaviour where mindreaders are, or appear to be, in a position to interact. A consequence is that revisions and extensions are needed to standard theories of the evidential basis of mindreading. The view also has consequences for understanding how abilities to interact combined with comparatively simple forms of mindreading may explain the emergence, in evolution or development, of sophisticated forms of social cognition